Some allergic individuals produce antibodies from a particular class of immunoglobulin called IgE against harmless allergens (Shearer, W. T. and Huston, D. P., Allergy, Principles and Practice, 1:15-17, 1993.) Most of the allergic reaction is the result of the interactions between IgE, the corresponding allergen that this particular IgE is specific for, and the high affinity IgE receptor, Fc.epsilon.RI. Fc.epsilon.RI is expressed at the surface of basophils in the blood and mast cells in solid tissues (Adamczewski, M. and Kinet, J-P, Chemical Immunology, 59:173-190, 1994.) When an allergen interacts with its specific IgE already bound to Fc.epsilon.RI on a cell, the cell is activated. This activation results in the production and release by the cell of allergy mediators, such as histamine, scrotonin, lipid mediators. The mechanism is responsible for a variety of clinical syndromes, including allergic rhinitis, asthma, atopic dermatitis, anaphylactic shock.
Fc.epsilon.RI is a tetrameric receptor composed of an IgE-binding .alpha. chain, a .beta. chain and a dimer of .gamma. chains (Adamczewski, M. and Kinet, J-P, Chemical Immunology, 59:173-190, 1994). Both the .beta. and .gamma. chains are responsible for generating cell-activating signals when an allergen binds to a receptor-bound IgE molecule (Scharenberg and Kinet, Human Basophils and Mast Cells; Biological Aspects, 61:72-87, 1995). The IgE binding site is located in the extracellular portion of the .alpha. chain (Hakimi et al., J. Biol. Chem., 265:3822079-22081, 1990, Blank et al., J. Biol. Chem. 266:2639-2646 1991), as shown by the binding of IgE to the soluble form of the .alpha. cabin, termed herein Fc.epsilon.RI .alpha., comprising only its extracellular portion made by genetic engineering, with the same characteristics as the tetrameric Fc.epsilon.RI.
IgE-mediated reactions are responsible for many allergic diseases, such as rhinitis (hay fever), asthma, urticaria, and atopic dermatitis. Intervention at the level of IgE and Fc.epsilon.RI interaction may prevent the IgE mediated immune responses that lead to allergic disorders. Previously, other investigators have tried to produce competitive inhibitors using IgE peptide analogs (Noriki, et al., FEBS Let., 319:225-228, 1993). For example, human soluble Fc.epsilon.RI .alpha.-chain inhibited human IgE binding Fc.epsilon.RI on Chinese hamster ovary cells and blocked passive cutaneous anaphylaxis reaction in vivo (Haak-Frendscho, et al., J. Immunol., 151:351-358, 1993). However, peptides and proteins generally are difficult to be formulated into drugs because of their unfavorable bioavailability, Anti-IgE antibodies have been used to remove IgE from circulation for the treatment of IgE mediated allergies (Chang, et al., BioTechnology, 8:122-126, 1990). Although antibodies have longer half-lives than proteins, they will elicit immunologic responses, require intravenous injection, and they are expensive to manufacture. The third option to inhibit IgE mediated immune responses would be to use small chemical inhibitors that can block the interaction between IgE and Fc.epsilon.RI .
It is the object of this invention to provide chemical compositions for antagonizing the interaction between IgE and Fc.epsilon.RI. It is another object of this invention to provide a method for antagonizing the interaction between IgE and Fc.epsilon.RI in which the antagonization is effective to prevent IgE-mediated response, is effective to inhibit mediator release from cells, and is effective to block the anaphylactic reaction in vivo. It is still another object of the invention, to provide an in vitro diagnostic for measuring antibodies against Fc.epsilon.RI.